1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diarylpyrrolidine, piperidine and homopiperidineacetamides and acetonitriles

ABSTRACT

Novel 1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diaryl-pyrrolidine, piperidine and homopiperidineacetamides and acetonitriles having the formula: ##STR1## wherein; n is zero, one or two; 
     X is oxygen or sulfur; 
     Z is ##STR2## p is 0 to 5 inclusive with the proviso that when Z is ##STR3##  p is at least one; Y is aminocarbonyl or cyano; 
     Ar 1  and Ar 2  are 2, 3 or 4-pyrido, phenyl or substituted phenyl; 
     R is hydrogen or loweralkyl; 
     R 1 , R 2  and R 3  are hydrogen, cycloalkyl, loweralkyl, phenyl, substituted phenyl, phenylloweralkyl, and R 2  and R 3  taken with the adjacent nitrogen may form a heterocyclic residue, and diastereoisomers when possible and pharmaceutical salts; and the method and pharmaceutical compositions for treating cardiac arrhythmias therewith are disclosed.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to novel 1-[(aminoalkyl andaminoalkylamino)carbonyl andthiocarbonyl]-α,α-diphenyl-3-pyrrolidineacetamides and acetonitriles andcorresponding 3 and 4-piperidine and homopiperidineacetamides andacetonitriles and a process for administering the same to a livinganimal body for the cardiac antiarrhythmic effect and pharmaceuticalmethods and compositions associated therewith.

2. Information Disclosure Statement

3-Pyrrolidinyl-α,α-diphenylacetamides, acetonitriles and methanes havingantiarrhythmic activity are disclosed in U.S. Pat. No. 4,002,766 andhave the general formula: ##STR4## wherein R is selected from hydrogen,loweralkyl, lowercycloalkyl or phenylloweralkyl; R¹ is hydrogen orloweralkyl; Ar is phenyl and among the radicals disclosed for Y arecarbamoyl and cyano. In contrast, while the pyrrolidine compounds in thepresent invention have similarly positioned carbamoyl or cyano radicals,the substituents at the one position are entirely different, having atleast a carbonyl or thiocarbonyl interposed and a terminal amino group.

OBJECTS AND SUMMARY OF THE INVENTION

The novel compounds of this invention have the formula: ##STR5##wherein; n is selected from zero, one or two;

X is selected from oxygen or sulfur;

Z is selected from ##STR6## p is selected from 0 to 5 inclusive with theproviso that when Z is ##STR7## p is at least one; Y is selected fromaminocarbonyl or cyano;

Ar¹ and Ar², which may be the same or different, are selected from thegroup consisting of 2, 3 or 4-pyrido, phenyl or phenyl substituted by 1to 3 radicals which may be the same or different selected fromloweralkyl, loweralkoxy, halogen or trifluoromethyl;

R is selected from hydrogen or loweralkyl;

R¹, R² and R³ are selected from the group consisting of hydrogen,cycloalkyl, loweralkyl, phenyl, phenyl substituted by halogen,loweralkyl, or loweralkoxy and phenyl-loweralkyl wherein phenyl may besubstituted by halogen, loweralkyl or loweralkoxy and R¹, R² and R³ maybe the same or different, and R² and R³ taken together with the adjacentnitrogen atom may form a heterocyclic residue selected from pyrrolidino,piperidino, 4-phenylpiperidino, 2,6-diloweralkyl-piperidino,4-hydroxy-4-phenylpiperidino, 4-cyano-4-phenylpiperidino,4-phenyl-1,2,3,6-tetrahydropiperidino, piperazino,4-loweralkylpiperazino, 4-phenylpiperazino,(4-phenylloweralkyl)-piperazino, or 4-morpholino radicals;

and when the side group ##STR8## is in the 3-position and Ar¹ and Ar²are dissimilar, the diastereoisomers thereof; and the pharmaceuticallyacceptable acid addition salts thereof.

The 1-[(aminoalkyl)carbonyl and thiocarbonyl]-α,α-diarylpyrrolidine,piperidine and homopiperidineacetamides and acetonitriles encompassed byFormula I wherein Z is --CH₂ --, have the formula: ##STR9## wherein n,Ar¹, Ar², Y, X, R, R² and R³ are as defined under Formula I and p isselected from zero to 5 inclusive and the salts and isomers of FormulaI.

The 1-[(aminoalkylamino)carbonyl andthiocarbonyl]-α,α-diarylpyrrolidine, piperidine and homopipiridineacetamides and nitriles encompassed by Formula I wherein Z is ##STR10##have the formula: wherein Ar¹, Ar², Y, X, R, R¹, R² and R³ are asdefined under Formula I and p is selected from 1 to 5 inclusive and thesalts and isomers of Formula I.

In the further definition of symbols in the formulas hereof and wherethey appear elsewhere throughout this specification and claims, theterms have the following significance.

The term "loweralkyl" as used herein includes straight and branchedchain radicals of up to eight carbons inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals and thelike. The term "loweralkoxy" has the formula "--O--loweralkyl."

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing 3 to 9 carbon atoms inclusive and includes suchgroups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclohexyl, cycloheptyl and the like.

The term "halogen" when referred to herein includes fluorine, chlorine,bromine and iodine, preferably fluorine, chlorine and bromine.

"Pharmaceutically acceptable acid addition salts" are those salts formedby the compounds with any acid which is physiologically compatible inwarm-blooded animals, such salts being formed by either strong or weakacids. Representative of strong acids are hydrochloric, hydrobromic,sulfuric and phosphoric acids. Representative of weak acids are fumaric,maleic, succinic, tartaric, oxalic, citric, hexamic and the like.

The compounds of the present invention exhibit cardiac antiarrhythmicactivity in dogs in the Ouabain and Ligation arrhythmia models asexplained more fully hereinbelow under "Pharmacology."

The method of treating cardiac arrhythmias in living animals comprisesadministering the compounds of Formula I to a living animal body forcardiac antiarrhythmia effect in an effective amount to controlarrhythmia as set forth hereinbelow under "Pharmaceutical Compositionsand Administration." The compounds of Formula I wherein Y is anacetamido radical are preferred for their antiarrhythmic effect.

It is therefore an object of the present invention to provide certainnovel 1-[(aminoalkyl)carbonyl and thiocarbonyl]-α,α-diarylpyrrolidine,piperidine and homopiperidineacetamides and acetonitriles, methods ofpreparing the same and methods and compositions for treating cardiacarrhythmias in living animals therewith.

Another object is to provide certain novel 1-[(aminoalkylamino)carbonyland thiocarbonyl]-α,α-diarylpyrrolidine, piperidine andhomopiperidineacetamides and acetonitriles, methods of preparing thesame and methods and compositions for treating cardiac arrhythmias inliving animals therewith.

Additional objects will be apparent to one skilled in the art and stillother objects will become apparent hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds as composition of matter set forth in Formula Iabove are utilized in pharmaceutical compositions in the novel method oftreating living animals in an amount effective for controlling cardiacarrhythmias.

The 1-[(aminoalkyl)carbonyl and thiocarbonyl] derivatives of Formula Iaencompassed by Formula I are prepared by Method A which is representedby the following equation: ##STR11## wherein Ar¹, Ar², Y, X, p, n, R, R²and R³ are selected from the values assigned under Formula I.

Generally, in Method A a 1-unsubstituted heterocyclicamine acetamido oracetonitrile (II) are reacted with a dihalo compound: ##STR12## in thepresence of base such as sodium or potassium carbonate in a suitablesolvent. The product mix is then reacted with an amine

    NHR.sup.2 R.sup.3                                          III

at room temperature for several hours and then concentrated. The residueis then partitioned between dilute aqueous base and a suitable solventsuch as methylene chloride. The solvent layer is dried and concentratedto give the free base of compounds of Formula Ia which may be convertedto acid addition salts in a suitable solvent. The salts may berecrystallized from mixtures of suitable solvents.

The 1-(aminoalkylamino)carbonyl derivatives of Formula Ib encompassed byFormula I are prepared by Methods B and C.

Method B is represented by the following equation: ##STR13## whereinAr¹, Ar², Y, X, p, n, R, R¹, R² and R³ are selected from the valuesassigned under Formula I with the proviso that R², R³ =alkyl or aryl andR¹ =H.

Generally, in Method B an alkyldiamine, V, is reacted first with1,1-carbonyldiimidazole (or 1,1-thiocarbonyldiimidazole) in a suitablesolvent (e.g., tetrahydrofuran) at room temperature followed by reactionat gentle reflux with the 1-unsubstituted-heterocyclicamine acetamide oracetonitrile (II). Usually, reaction is effected by refluxing forseveral hours after which the mixture is cooled and concentrated. Theresidue is taken up in a solvent such as methylene chloride and washedto remove impurities and the product obtained by evaporating themethylene chloride to obtain the free base of compounds of Formula Iband, if desired, converting to an acid addition salt in a suitablesolvent and recrystallizing from a suitable solvent mixture. The methodis illustrated in Example 6.

Method C is represented by the following equation: ##STR14## whereinAr¹, Ar², Y, X, p, R, R¹, R² and R³ are selected from values assignedunder Formula I with the proviso that when R¹ is not hydrogen, R² and R³must be other than hydrogen, or R¹ is the same as R², and R³ ishydrogen.

Generally, in Method C the 1-unsubstituted heterocyclic compound isreacted with phosgene (or thiophosgene) in a suitable organic solventplus Proton Sponge®, which is 1,8-bis(dimethylamino)naphtylene followedby extraction (washing) with dilute sulfuric acid, and the organic layeris dried and evaporated to an oil. The oil is dissolved intetrahydrofuran and reacted with an amine of Formula V. The reactionmixture is stripped to dryness and the residue is partitioned betweenwater and a suitable organic solvent. Evaporation of the solvent yieldsthe crude free base, Ib.

As can be seen in the foregoing process description and followingexamples, compounds of Formula I are either isolated as the free base byevaporating or crystallizing or as an acid addition salt by reactionwith the desired acid using conventional means, crystallizing andrecrystallizing from a suitable solvent or mixture or solvents, usuallyan alcohol and an ester or ether.

Salts of compounds of Formula I, Ia and Ib may be converted to the freebase by partitioning between a solvent such as methylene chloride and anaqueous base such as sodium hydroxide and evaporating the solvent layerin vacuo.

As mentioned above, the prior art discloses methods of preparing1-unsubstituted hydroxyhomopiperidines which are used to prepare thehomopiperidine derivatives of this invention.

A general method for the preparation of 1-unsubstituted-3 and4-[α,α-diarylacetonitrilo and acetamido]pyrrolidines, piperidines andhomopiperidines is outlined by schematic equation in Chart I. ##STR15##

Another method for the preparation of1-unsubstituted-3-[α,α-diarylacetonitrilo and acetamido]pyrrolidines and1-unsubstituted 4-[α,α-diarylacetonitrilo and acetamido]piperidines andhomopiperidines is outlined in Chart II. ##STR16##

The following preparations serve to illustrate the synthesis of certainprecursors required in making the compounds of Formula I but are notlimiting as to scope. The preparation of certain1-unsubstituted-α,α-diarylacetonitrilo and acetamido-pyrrolidinylprecursors is taught in U.S. Pat. No. 4,002,766.

PREPARATION 1 α,α-Diphenyl-1-(phenylmethyl)-3-pyrrolidineacetonitrile

The title compound was prepared from 1-(phenylmethyl)-3-pyrrolidinol,methanesulfonylchloride, triethylamine and sodium diphenylacetonitrileby the procedure of U.S. Pat. No. 3,192,210, b.p. 215-218/0.01 mm.

PREPARATION 21-[(4-Methylphenyl)sulfonyl]-3-piperidinol-4-methylphenylsulfonate ester

A solution of 73.5 g (0.728 mole) of 3-hydroxy piperidine and 350 g(1.84 mole) of p-toluenesulfonyl chloride in 1 liter of pyridine wasstirred at room temperature for 17.5 hr. The solution was quenched in 1liter of water. The aqueous mixture was extracted with several portionsof methylene chloride and the combined methylene chloride layers wereextracted with several portions of 1M sulfuric acid and then withseveral portions of 1M sodium hydroxide. The organic solution was driedover magnesium sulfate and the solvent was removed in vacuo to give anoil residue. Crystalline product was obtained from the oil residue usingthe solvent pair, diethyl ethermethylene chloride, m.p. 132°-133° C.

Analysis: Calculated for C₁₉ H₂₃ NO₅ S₂ : C, 55.73; H, 5.66; N, 3.42.Found: C, 55.79; H, 5.69; N, 3.38.

PREPARATION 3 3-(Cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid,methyl ester

To a solution of 36.5 g (0.10 mole) ofα-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 8.7 g (0.11mole) of pyridine in methylene chloride was added dropwise at 25° C.,10.4 g (0.11 mole) of methyl chloroformate. The solution was refluxedfor 16 hr. To the refluxing solution was added 26.1 g (0.33 mole) ofpyridine and 31.2 g (0.33 mole) additional methyl chloroformate. Heatingat reflux was continued for 5 hr. The mixture was cooled and washed fourtimes with water. The methylene chloride layer was dried andconcentrated in vacuo. The residual oil was crystallized twice from amix of petroleum ether (30°-60°) and isopropanol to give 22 g (68%) oftitle product, m.p. 133°-135° C.

Analysis: Calculated for C₂₀ H₂₀ N₂ O₂ : C, 74.98; H, 6.29; N, 8.74.Found: C, 75.03; H, 6.44; N, 8.66.

PREPARATION 4 α,α-Diphenyl-3-pyrrolidineacetamido oxalate

A stirred solution of 22.0 g (0.060 mole) ofα,α-diphenyl-3-pyrrolidineacetonitrile in 100 ml of conc. sulfuric acidwas heated at 70° C. for 24 hr and then cooled. The cold reactionmixture was poured over ice and basified with 50% sodium hydroxide andice. The mixture was extracted with chloroform. The chloroform extractwas washed with water, dried over sodium sulfate and concentrated invacuo to give the free base of the title compound. The free base wasreacted with oxalic acid and crystallized from isopropyl alcohol to give15 g of title product, m.p. 216°-218.5° C.

PREPARATION 5 3-(Cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid,phenyl ester

To a solution of 47 g (0.13 mole) ofα-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 10.58 g (0.13mole) of pyridine in 400 ml of methylene chloride was added, dropwise at0° C., 62.7 g (0.39 mole) of phenyl chloroformate. The reaction mixturewas refluxed for 16 hr. The mixture was cooled and washed 3 times withwater and twice with dilute sodium hydroxide solution. The methylenechloride layer was then dried, filtered and concentrated in vacuo. Theresulting solid was recrystallized twice from ethyl acetate to give 23 g(50%) of title compound, m.p. 154°-155° C.

Analysis: Calculated for C₂₅ H₂₂ N₂ O₂ : C, 78.51; H, 7.32; N, 5.79.Found: C, 78.31; H, 7.43; N, 5.74.

PREPARATION 6 α,α-Diphenyl-3-pyrrolidineacetamide

A solution of 3.0 g (0.008 mole) of3-(cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid phenyl ester in 100ml of 90% sulfuric acid was stirred at 70° C. for 20 hr. The reactionmixture was cooled, poured over ice and basified by adding, alternately,50% sodium hydroxide and ice. The mixture was extracted with chloroform.The chloroform extract was washed with water, dried over sodium sulfateand concentrated in vacuo. The residue was crystallized in ethylacetate. Recrystallization from ethyl acetate-ethanol gave 1.4 g (65%)of title product, molecular ion at 281 by mass spectrometer analysis.

PREPARATION 7 α,α-Diphenyl-3-pyrrolidineacetonitrile oxalate [1:1]Preparation of Lithium n-propyl-Mercaptide Reagent

To a mixture of 8.9 g (1.12 mole) of lithium hydride in 350 ml ofhexamethylphosphoramide under a nitrogen atmosphere was added, dropwiseat 10° C., 78.65 g (1.03 mole) of n-propanethiol. Stirring was continuedfor 3 hr and the mixture was filtered under nitrogen atmosphere. Thereagent was titrated with 0.1N hydrochloric acid to a phenolphthaleinend point. The normality of the reagent was 0.74N.

To 320 ml (0.24 mole) of the foregoing lithium n-propyl mercaptidereagent was added, portionwise at 25° C., 14 g (0.044 mole) of3-(cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid, methyl ester.Stirring was continued at 25° C. for 16 hr and then at 50°-60° C. for 2hr. The mixture acidified with 6N hydrochloric acid and then stirred at60°-70° C. for 20 min. The mixture was cooled and extracted 3 times withisopropyl ether. The aqueous layer was separated, basified with dilutesodium hyroxide and extracted 3 times with isopropyl ether. These lastether extracts were washed 3 times with water, dried and concentrated invacuo. The residue was reacted with oxalic acid crystallizing theoxalate salt from isopropanol-water to give a 64% yield of the titlecompound. A portion was recrystallized from isopropanol-water, m.p.181°-184° C. (with decomposition).

Analysis: Calculated for C₂₀ H₂₀ N₂ O₄ : C, 68.17; H, 5.72; N, 7.95.Found: C, 68.05; H, 5.68; N, 7.93.

PREPARATION 8 α,α-Diphenyl-1-phenylmethyl-3-pyrrolidineacetamide

To 250 ml of concentrated sulfuric acid under agitation was added,slowly at 70° C., 170 g (0.48 mole) ofα-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile. Stirring wascontinued for 16 hr at 75°-80° C. The solution was cooled and pouredinto a mixture of ice, 50% sodium hydroxide solution and chloroform. Thechloroform layer was separated and the aqueous phase extracted threemore times with chloroform. The combined chloroform layers were driedand concentrated in vacuo to give 188 g of residual oil. A portion ofthe oil was crystallized in isopropanol and the solid recrystallizedfrom a mix of isopropanol and isopropyl ether to give a light brownsolid, m.p. 135°-138° C.

Analysis: Calculated for C₂₅ H₂₆ N₂ O: C, 81.05; H, 7.07; N, 7.56.Found: C, 80.95; H, 7.21; N, 7.59.

PREPARATION 9 α,α-Diphenyl-3-pyrrolidineacetamide maleate [1:1]

A solution of 1.13 g of 1-benzyl-α,α-diphenyl-3-pyrrolidineacetamide in50 ml of methanol was subjected to catalytic hydrogenation (over 0.5 gof 10% palladium-on-charcoal catalyst) at 75° C. overnight in a Parrhydrogenation apparatus. The mixture was filtered and the filtrate wasconcentrated to give 0.783 g (80%) free base of the title compound aslight tan gum. The mass spectra and infrared spectra were consistentwith the structure. To a methanol solution of a portion of the free basewas added a methanolic solution of maleic acid. The solution wasconcentrated to remove methanol and the residue crystallized. The solidwas recrystallized twice from isopropanol-diethyl ether. The solid wasdried at 110°/0.1 mm for 3 hr. The product liquefied over a range of110°-145° C.

Analysis: Calculated for C₂₂ H₂₄ N₂ O₅ : C, 66.65; H, 6.10; N, 7.07.Found: C, 66.79; H, 6.05; N, 7.04.

PREPARATION 10 α,α-Diphenyl-3-pyrrolidineacetamide N-cyclohexylsulfamatehydrate [3:2]

A methanolic solution of 1.15 g of α,α-diphenyl-3-pyrrolidineacetamideand 0.735 g of hexamic acid was prepared and the methanol was evaporatedfrom the solution to give a crystalline residue. The residue wasrecrystallized from ethanol, m.p. 103°-106° C.

Analysis: Calculated for C₄₈ H₇₂ N₆ O₁₁ : C, 59.24; H, 7.46; N, 8.64.Found: C, 58.97; H, 6.98; N, 8.51.

PREPARATION 11 α,α-Diphenyl-1-(phenylmethyl)-4-piperidineacetonitrilehydrochloride

To a prewashed slurry of 8.0 g (0.19 mole) of 57% sodium hydride in 300ml of dimethylsulfoxide was added 32.8 g (0.17 mole) ofdiphenylacetonitrile. The solution was heated at 65° C. for 1 hr, duringwhich time the solution developed a deep red color. To the reactionmixture was added 55.90 g (0.16 mole) of 1-(phenylmethyl)-4-piperidinolester with 4-methylbenzenesulfonic acid in 50 ml of dimethylsulfoxideand the solution was stirred overnight at 60° C. The solution was cooledand poured into 1 liter of water. The aqueous solution was extractedthree times with 150 ml portions of toluene. The toluene extracts werecombined and 500 ml of 1N sulfuric acid was added. A gummy residueprecipitated which was separated and partitioned with methylene chlorideand 10% aqueous sodium hydroxide. The aqueous layer was extracted withmethylene chloride and the combined methylene chloride extracts weredried over magnesium sulfate and concentrated to give 35.0 g (57%) offree base of the title compound as tan solid, m.p. 138°-142° C. Aportion of the free base in methanol was reacted with ethereal hydrogenchloride to give the hydrochloride salt, m.p. >250° C.

Analysis: Calculated for C₂₆ H₂₇ ClN₂ : C, 77.50; H, 6.75; N, 6.95.Found: C, 77.09; H, 6.76; N, 7.04.

PREPARATION 12α,α-Diphenyl-1-[4-(methylphenyl)sulfonyl]-3-piperidineacetonitrile

To a slurry of 0.15 g (0.012 mole) of prewashed sodium hydride in 100 mlof toluene was added 2.10 g (0.011 mole) of diphenylacetonitrile. Thesolution was refluxed for 2 hrs and 4.0 g (0.010 mole) of1-[(4-methylphenyl)sulfonyl]-3-piperidinol-(4-methylphenyl)sulfonateester in 100 ml of toluene was added. The solution was refluxed for 18hr, cooled, washed three times with 100 ml portions of water and driedover magnesium sulfate. The solution was evaporated to a gummy residuewhich was crystallized from absolute ethanol to give 2.50 g (58%) of apale yellow powder, m.p. 135°-136° C.

Analysis: Calculated for C₁₉ H₂₆ N₂ O₂ S: C, 72.53; H, 6.09; N, 6.51.Found: C, 72.79; H, 6.10; N, 6.52.

PREPARATION 13 α,α-Diphenyl-3-piperidineacetonitrile hydrochloride

A solution of 5.00 g (0.012 mole) ofα,α-diphenyl-1-[4-(methylphenyl)sulfonyl]-3-piperidineacetonitrile, 60ml of 48% hydrobromic acid and about 5 g phenol (excess) was refluxedfor 3.5 hr. The solution was cooled, poured onto ice and made basic withan excess of 50% sodium hydroxide. The mixture was extracted with three150 ml portions of methylene chloride. The combined methylene chloridelayers were dried and concentrated to give a black oily residue. Theresidue was taken up in 1:1 isooctane/toluene solution and the mixturewas extracted with 10% aqueous hydrochloric acid solution. The acidicextract was made basic with 10% sodium hydroxide and extracted withmethylene chloride. The extracts were dried over magnesium sulfate andconcentrated to give 1.70 g (84%) of the free base of the title compoundas a glassy residue. The free base was dissolved in isopropyl alcoholand reacted with ethereal hydrogen chloride to give the hydrochloridesalt. The salt was recrystallized from ethanol/ethyl acetate to give1.79 g (48%) of the title product, m.p. 171°-177° C.

Analysis: Calculated for C₁₉ H₂₁ ClN₂ : C, 72.95; H, 6.77; N, 8.95.Found: C, 72.64; H, 6.73; N, 8.90.

PREPARATION 14 4-Cyanodiphenylmethyl)-1-piperidinecarboxylic acid phenylester

To a solution of 34.0 g (0.093 mole) ofα,α-diphenyl-1-(phenylmethyl)-4-piperidineacetonitrile in 300 ml ofmethylene chloride was added dropwise to 15.70 g (0.10 mole) ofphenylchloroformate in 100 ml of methylene chloride. The solution wasstirred 3 hr at room temperature, after which 11.10 g (0.11 mole) oftriethylamine was added. The solution was stirred additionally for 1 hr,washed with 200 ml of water followed by 100 ml of 10% hydrochloric acidand dried over magnesium sulfate. The methylene chloride layer wasconcentrated to give a tan colored paste. The paste was recrystallizedfrom isopropyl alcohol to give 19.70 g (54%) of solid. A portion of thesolid was recrystallized from isopropyl alcohol, m.p. 141°-143° C.

Analysis: Calculated for C₂₆ H₂₄ N₂ O₂ : C, 78.76; H, 6.10; N, 7.06.Found: C, 78.38; H, 6.27; N, 7.01.

PREPARATION 15 α,α-Diphenyl-4-piperidineacetamide fumarate monohydrate

A solution of 18.50 g (0.046 mole) of4-(cyanodiphenylmethyl)-1-piperidinecarboxylic acid phenyl ester in 100ml of 90% sulfuric acid was heated at 65° C. for 18 hr and 90° C. for 6hr. The mixture was cooled, poured onto ice and made basic with excess50% sodium hydroxide. The aqueous solution was extracted with three 150ml portions of chloroform. The combined chloroform extract was driedover magnesium sulfate and concentrated to give a residue whichcrystallized on standing. Recrystallization of the residue fromethanol/ethyl acetate gave 6.10 g (45%) of the free base of the titlecompound. A 1 g portion was reacted with fumaric acid, crystallizingfrom methanol-diethyl ether to yield 1.0 g of the salt, m.p. 172°-175°C. (softens at 158° C.).

Analysis: Calculated for C₂₃ H₂₆ N₂ O₆ : C, 64.47; H, 6.59; N, 6.54.Found: C, 64.76; H, 6.13; N, 6.55.

PREPARATION 16 α,α-Diphenyl-3-piperidineacetamide hemifumaratehemihydrate

A solution of 2.3 g (0.0086 mole) of crudeα,α-diphenyl-3-piperidineacetonitrile hydrochloride in 50 ml of 90%sulfuric acid was heated at 80° C. for 18 hr. The solution was cooled,made basic with excess 50% sodium hydroxide and extracted with methylenechloride. The extract was dried over magnesium sulfate and concentratedto yield 1.5 g (59%) of crude free base of the title compound. Thefumarate was prepared in methanol using 0.5 equivalent of fumaric acidand adding diethyl ether to precipitate and give 0.50 g (16%) of titleproduct,

m.p. >250° C.

Analysis: Calculated for C₂₁ H₂₅ N₂ O₃.5 : C, 69.78; H, 6.97; N, 7.75.Found: C, 69.75; H, 6.90; N, 7.68.

PREPARATION 17 1-(Phenylmethyl)-4-piperidinol ester with4-methylbenzenesulfonic acid maleate [1:1]

A solution of 100 g (0.524 mole) of N-benzyl-4-hydroxypiperidine and 13g (0.684 mole) of tosylchloride in 600 ml of pyridine was stirred atroom temperature overnight. One liter of methylene chloride and 500 mlof 0.5M aqueous sodium hydroxide were added to the reaction mixture. Thereaction mixture was stirred for 10 min and the phases were separated.The methylene chloride layer was extracted with several portions ofdilute sodium hydroxide, dried over magnesium sulfate and evaporated invacuo to give an oil, the free base of the title compound. The free basewas converted to the maleate salt which was recrystallized frommethylene chloride-diethyl ether to give white crystalline solid, m.p.159°-160° C.

Analysis: Calculated for C₂₃ H₂₇ NO₇ S: C, 59.86; H, 5.90; N, 3.04.Found: C, 59.79; H, 5.86; N, 2.95.

PREPARATION 18α-(4-Chlorophenyl)-α-[1-(phenylmethyl)-3-pyrrolidinyl]-2-pyridineacetonitrileα isomer*

To a solution of 136 g (0.77 mole) of 1-benzyl-3-pyrrolidinol and 78 g(0.79 mole) of triethylamine in 600 ml of dry benzene was added dropwise8.86 g (0.77 mole) of methanesulfonyl chloride while cooling with an icebath. The ice bath was removed and the mixture stirred 1 hr. andfiltered. The filter cake was washed twice with 100 ml of benzene.

In a separate flask, 175 g (0.77 mole ofα-(4-phenyl)-2-pyridylacetonitrile in 300 ml of dry toluene was addeddropwise to a suspension of 40.3 g (0.84 mole) of 50% sodium hydride(mineral oil was removed by washing with ligroin) in 800 ml of drytoluene at 80° C. The mixture was heated to 80°-85° C. for 1 hr. and thebenzene solution of 1-benzyl-3-pyrrolidinemethanesulfonate (preparedabove) was added dropwise while maintaining the temperature. Thesolution was stirred for 2 hr. at 85° C., cooled and extracted twicewith water. The organic layer was dried over sodium sulfate anddistilled. Yield 196 g (65%), b.p. 240°-250° C./0.5 mm.

A sample (15 g) was chromatographed on the HPLC (Water Prep LC/System500 A) using Prep Pak 500 silica column and isopropyl ether. An impuritywas first to emerge followed by the two diastereomers which werepartially separated. That portion of the first emerging isomer which wasshown by T.L.C. (silica gel; ethyl acetate) to be pure was collected andconcentrated. Yield 4 g (27%) of racemic mixture.

Analysis: Calculated for C₂₄ H₂₂ N₃ Cl: C, 74;31; H, 5.72; N, 10.83.Found: C, 74.38; H, 5.69; N, 10.96.

PREPARATION 19α-(4-Chlorophenyl)-α-[1-(phenylmethyl)-3-pyrrolidinyl]-2-pyridineacetonitrileβ isomer*

To a solution of 136 g (0.77 mole) of 1-benzyl-3-pyrrolidinol and 78 g(0.79 mole) of triethylamine in 600 ml of dry benzene was added dropwise8.86 g (0.77 mole) of methanesulfonyl chloride while cooling with an icebath. The ice bath was removed and the mixture stirred 1 hr. andfiltered. The filter cake was washed twice with 100 ml of benzene.

In a separate flask 175 g (0.77 mole) ofα-(4-phenyl)-2-pyridylacetonitrile in 300 ml of dry toluene was addeddropwise to a suspension of 40.3 g (0.84 mole) of 50% sodium hydride(mineral oil was removed by washing with ligroin) in 800 ml of drytoluene at 80° C. The mixture was heated to 80°-85° C. for 1 hr. and thebenzene solution of 1-benzyl-3-pyrrolidinemethanesulfonate (preparedabove) was added dropwise while maintaining the temperature. Thesolution was stirred for 2 hr. at 85° C., cooled and extracted twicewith water. The organic layer was dried over sodium sulfate anddistilled. Yield 196 g (65%), b.p. 240°-250° C./0.5 mm.

A sample (15 g) was chromatographed on the HPLC (Water Prep LC/System500 A) using Prep Pak 500 silica column and isopropyl ether. An impuritywas first to emerge followed by the two diastereomers which werepartially separated. That portion of the second emerging isomer whichwas shown by T.L.C. (silica gel; ethyl acetate) to be pure was collectedand concentrated. Yield 4.5 g (30%) of racemic mixture.

Analysis: Calculated for C₂₄ H₂₂ N₃ Cl: C, 74.31; H, 5.72; N, 10.83.Found: C,74.33; H, 5.71; N, 10.95.

PREPARATION 20 a AND b3-[α-(4-Chlorophenyl)-α-(2-pyridinyl)-cyanomethyl]-1-pyrrolidinecarboxylicacid, phenyl ester α isomer and β isomer

Following the procedure of Preparation 5, the title compound is obtainedby reactingα-(4-chlorophenyl)-α-[1-(phenylmethyl)-3-pyrrolidinyl]-2-pyridineacetonitrileα isomer (Preparation 18) with phenylchloroformate in pyridine-methylenechloride solvent.

The β-isomer is prepared from the corresponding starting materialα-(4-chlorophenyl)-α-[(phenylmethyl)-3-pyrrolidinyl]-2-pyridineacetonitrileβ-isomer (Preparation 19).

PREPARATION 21 a AND bα-(4-Chlorophenyl)-α-(2-pyridinyl)-3-pyrrolidineacetamide α isomer and βisomer

Following the procedure of Preparation 15, the title compound isprepared by subjecting3-[α-(4-chlorophenyl)-α-(2-pyridinyl)-cyanomethyl]-1-pyrrolidinecarboxylicacid, phenyl ester α-isomer (Preparation 20a) to hydrolysis with hot 90%sulfuric acid.

The β-isomer is prepared from the corresponding starting material:3-[α-(4-chlorophenyl)-α-(2-pyridinyl)-cyanomethyl]-1-pyrrolidinecarboxylicacid, phenyl ester β-isomer (Preparation 20b).

PREPARATION 22 a AND b

Following the procedure of Preparation 2,

3-hydroxyhomopiperidine, and

4-hydroxyhomopiperidine

are reacted with p-toluenesulfonyl chloride to give the following:

(a)1-[(4-methylphenyl)sulfonyl]-3-homopiperidinol-4-methylphenylsulfonateester hydrochloride, and

(b)1-[(4-methylphenyl)sulfonyl]-4-homopiperidinol-4-methylphenylsulfonateester hydrochloride.

PREPARATION 23 a AND b

Following the procedure of Preparation 12,

1-[(4-methylphenyl)sulfonyl]-3-homopiperidinol-4-methylsulfonate ester,and

1-[(4-methylphenyl)sulfonyl]-4-homopiperidinol-4-methylphenylsulfonateester

are reacted with sodium hydride and diphenylacetonitrile to give thefollowing:

(a)α,α-diphenyl-1-[4-(methylphenyl)sulfonyl]-3-homopiperidinolacetonitrile,and

(b)α,α-diphenyl-1-[4-(methylphenyl)sulfonyl]-4-homopiperidinolacetonitrile.

PREPARATION 24 a AND b

Following the procedure of Preparation 13,

α,α-diphenyl-1-[4-(methylphenyl)sulfonyl]-3-homopiperidinolacetonitrile,and

α,α-diphenyl-1-[4-(methylphenyl)sulfonyl]-4-homopiperidinolacetonitrile

are subjected to refluxing 48% hydrobromic acid in phenol to give thefollowing:

(a) α,α-diphenyl-3-homopiperidineacetonitrile, and

(b) α,α-diphenyl-4-homopiperidineacetonitrile which may be isolated ashydrochloride salts as in Preparation 13.

PREPARATION 25 a AND b

Following the procedure of Preparation 16,

α,α-diphenyl-3-homopiperidineacetonitrile, and

α,α-diphenyl-4-homopiperidineacetonitrile

are hydrolyzed with conc. sulfuric acid (90%) to give the following:

(a) α,α-diphenyl-3-homopiperidineacetamide, and

(b) α,α-diphenyl-4-homopiperidineacetamide.

The following examples serve to illustrate the preparation of the novelcompounds of Formula I, useful in treating cardiac arrhythmias in themethod of this invention. The scope of the invention is not, however,limited thereto.

EXAMPLE 11-[[(Dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamidehydrochloride hemihydrate

To a stirred solution of 7.0 g (0.025 mole ofα,α-diphenyl-3-pyrrolidineacetamide and 3.07 g of sodium carbonate in150 ml of tetrahydrofuran was added 3.05 g (0.027 mole) ofchloroacetylchloride. The solution was stirred 1.5 hr and 12 g (0.11mole) of 40% aqueous dimethyl-amine was added. The solution was stirredan additional 3 hr and then concentrated. The residue was taken up in100 ml of water and 50 ml of 10% aqueous sodium hydroxide and extractedwith methylene chloride. The extracts were dried over magnesium sulfateand concentrated to yield 8.00 g (88%) residue as crude free base of thetitle compound. The hydrochloride salt was prepared in isopropyl alcoholwith ethereal hydrogen chloride. Additional ether was added to totallyprecipitate the salt. Recrystallization from isopropyl alcohol-isopropylacetate gave 3.0 g (29%) of the hydrochloride hemihydrate, softeningpoint 183°-185° C., m.p. 192°-196° C.

Analysis: Calculated for C₂₂ H₂₉ ClN₃ O₂.5 : C, 64.30; H, 7.11; N,10.22. Found: C, 64.42; H, 7.05; N, 9.86.

EXAMPLE 2

Following the procedure of Example 1 but substituting the following forα,α-diphenyl-3-pyrrolidineacetamide:

α,α-diphenyl-3-piperidineacetamide, and

α,α-diphenyl-4-piperidineacetamide, there are obtained:

1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-piperidineacetamidehydrochloride, and

1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-4-piperidineacetamidehydrochloride.

EXAMPLE 3

Following the procedure represented by the above equations for Method Aand as in Example 1, but substituting the following forα,α-diphenyl-3-pyrrolidineacetamide:

α,α-diphenyl-3-pyrrolidineacetonitrile,

α,α-diphenyl-3-piperidineacetonitrile, and

α,α-diphenyl-4-piperidineacetonitrile

there are obtained:

1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-pyrrolidineacetonitrilehydrochloride,

1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-piperidineacetonitrilehydrochloride, and

1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-4-piperidineacetonitrilehydrochloride.

EXAMPLE 41-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamidefumarate hydrate

To a stirred solution of 3.89 g (0.024 mole) of 1,1'-carbonyldiimidazolein 100 ml of tetrahydrofuran was added 1.93 g (0.022 mole) ofN,N-dimethylethylenediamine. The solution was stirred at ambienttemperature for 1.5 hr and 5.60 g of α,α-diphenyl-3-pyrrolidineacetamidewas added. The solution was refluxed for 3.5 hr, cooled andconcentrated. The residue obtained was dissolved in methylene chloride,washed with water, dried over magnesium sulfate and concentrated to give8.40 g of crude free base of the title compound as white powdered glass.The free base was dissolved in isopropyl alcohol and reacted withfumaric acid. The solution was heated and isopropyl acetate was addeduntil the cloud point was reached. The solution was cooled and filteredto give the fumarate salt. The salt was air dried for 18 hr to give 3.50g (33%) of a white powder, m.p., softens 85°-90° C.; melts 120°-130° C.with decomposition.

Analysis: Calculated for C₂₇ H₃₆ N₄ O₇ : C, 61.35; H, 6.86; N, 10.60.Found: C, 61.54; H, 6.67; N, 10.51.

EXAMPLE 51-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-piperidineacetamidefumarate hemihydrate

A solution of 4.37 g (0.027 mole) of 1,1'-carbonyldiimidazole and 2.11 g(0.024 mole) of N,N-dimethylethylenediamine in 150 ml ofdimethylformamide was stirred for 1.5 hr at ambient temperature. To thesolution was added 6.40 g (0.021 mole) ofα,α-diphenyl-3-piperidineacetamide and the resulting solution wasrefluxed for 18 hr, cooled and concentrated. The residue was taken up in100 ml of methylene chloride and 50 ml of water. The layers wereseparated and the aqueous layer was extracted with 50 ml of methylenechloride. The combined extracts were dried over magnesium sulfate sndconcentrated to give 8.40 g of crude free base of the title compound.The free base was dissolved in isopropyl alcohol and reacted withfumaric acid. Diethyl ether was added to precipitate the fumarate salt.The salt was dissolved in methanol and diethyl ether was added untilprecipitation was complete. The salt was separated and air dried for 18hr to give 4.50 g (40%) of a white powder, m.p. 202°-203° C.

Analysis: Calculated for C₂₈ H₃₇ N₄ O₆.5 : C, 63.02; H, 6.99; N, 10.50.Found: C, 63.25; H, 7.00; N, 10.39.

EXAMPLE 61-[[[(2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamidefumarate sesquihydrate

To a stirred solution of 2.75 g (0.017 mole) of 1,1'-carbonyldiimidazolein 100 ml of tetrahydrofuran was added 1.32 g (0.015 mole) ofN,N-dimethylethylenediamine. The solution was stirred for 1.5 hr and4.00 g (0.013 mole) of α,α-diphenyl-4-piperidineacetamide in 50 ml oftetrahydrofuran was added. The solution was refluxed for 18 hr, cooledand concentrated. The residue was taken up in methylene chloride, andthe solution was washed with three 50 ml portions of water and extractedwith two 200 ml portions of 1N sulfuric acid. The acidic extracts weremade basic and extracted with methylene chloride. The methylene chlorideextracts were dried over magnesium sulfate and concentrated to give 3.40g of the free base of the title compound as a white glassy solid. Thefree base was recrystallized from ethyl acetate/ethyl alcohol to give1.90 g (35%) crystals. The crystalline solid was dissolved in methanoland reacted with fumaric acid. The fumarate salt was precipitated byaddition of diethyl ether to give 1.60 g (22%) crystals, m.p. softens80° C., melts 133°-135° C.

Analysis: Calculated for C₂₈ H₃₉ N₄ O₇.5 : C, 60.96; H, 7.13; N, 10.16.Found: C, 60.60; H, 6.78; N, 10.29.

EXAMPLE 71-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-homopiperidinoacetamide

Following the procedure of Example 5, and substitutingα,α-diphenyl-3-homopiperidineacetamide forα,α-diphenyl-3-piperidineacetamide, the title compound is prepared.

EXAMPLE 81-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-4-homopiperidinoacetamide

Following the procedure of Example 6, and substitutingα,α-diphenyl-4-homopiperidineacetamide for α,α-diphenyl-4-piperidine,the title compound is prepared.

EXAMPLE 91-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-homopiperidineacetonitrile

Following the procedure of Example 5, and substitutingα,α-diphenyl-3-homopiperidineacetonitrile forα,α-diphenyl-3-piperidineacetamide, the title compound is prepared.

EXAMPLE 101-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-4-homopiperidineacetonitrile

Following the procedure of Example 6 and substitutingα,α-diphenyl-4-homopiperidineacetonitrile forα,α-diphenyl-4-piperidineacetamide, the title compound is prepared.

EXAMPLE 111-[[(Dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-homopiperidineacetamide

Following the procedure of Example 1 and substitutingα,α-diphenyl-3-homopiperidineacetamide forα,α-diphenyl-3-pyrrolidineacetamide, the title compound is prepared.

EXAMPLE 121-[[(Dimethylamino)methyl]carbonyl]-α,α-diphenyl-4-homopiperidineacetamide

Following the procedure of Example 1 and substitutingα,α-diphenyl-4-homopiperidineacetamide forα,α-diphenyl-3-pyrrolidineacetamide, the title compound is prepared.

EXAMPLE 13 a AND b1-[[[2-(Dimethylamino)ethyl]amino]carbonyl]-α-(4-chlorophenyl),α-(2-pyridinyl)-3-pyrrolidinylacetamide α isomer and β isomer

Following the procedure of Example 4, the α and β isomers ofα-(4-chlorophenyl), α-(2-pyridinyl)-3-pyrrolidine acetamide as preparedby Preparations 21(a) and (b) are separately reacted with the reactionproduct of

(a) 1,1'-carbonyldiimidazole, and

(b) N,N-dimethylethylenediamine to give the title products.

EXAMPLE 14 a AND b1-[[(Dimethylamino)methyl]carbonyl]-α-(4-chlorophenyl),α-(2-pyridinyl)-3-pyrrolidineacetamide α isomer and β isomer

Following the procedure of Example 1, the α and β isomers of2-(4-chlorophenyl), α-(2-pyridinyl)-3-pyrrolidine acetamide as preparedby Preparations 21(a) and (b) are separately reacted in sequence with

(a) chloroacetylchloride, and

(b) dimethylamine to give the title compounds.

EXAMPLE 151-[[[2-(Dimethylamino)ethyl]amino]thiocarbonyl]-α,α-diphenyl-4-piperidineacetamidefumarate

Following the procedure of Example 6, and substituting1,1'-thiocarbonyldiimidazole for 1,1'-carbonyldiimidazole, the titlecompound is prepared.

EXAMPLE 16

Following the procedure of Example 6, and substituting the following forN,N-dimethylethylenediamine:

N,N,N'-trimethylethylenediamine,

N,N-dimethyl-N'-phenylmethylethylenediamine,

N,N-dimethyl-N'-phenylethylenediamine,

N,N-dimethyl-N'-cyclohexylethylenediamine,

1-(2-aminoethyl)-pyrrolidine,

1-(2-aminoethyl)-piperidine,

1-(2-aminoethyl)-4-phenylpiperidine,

1-(2-aminoethyl)-2,6-dimethylpiperidine,

1-(2-aminoethyl)-4-hydroxy-4-phenylpiperidine,

1-(2-aminoethyl)-4-phenyl-1,2,3,6-tetrahydropyridine,

1-(2-aminoethyl)-4-tertiarybutoxycarbonylpiperazine,

1-(2-aminoethyl)-4-methylpiperazine,

1-(2-aminoethyl)-4-phenylpiperazine,

1-(2-aminoethyl)-4-(phenylmethyl)-piperazine, and

4-(2-aminoethyl)-morpholine

there are obtained:

(a)1-[[[2-(dimethylamino)-1-methylethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(b)1-[[[2-(dimethylamino)-1-(phenylmethyl)ethyl]amino]carbonyl]-α,.alpha.-diphenyl-4-piperidineacetamide,

(c)1-[[[2-(dimethylamino)-1-phenylethyl]amino]carbonyl]α,α-diphenyl-4-piperidineacetamide,

(d)1-[[[2-(dimethylamino)-1-cyclohexylethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(e)1-[[[2-(pyrrolidin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(f)1-[[[2-(piperidin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(g)1-[[[2-(4-phenylpiperidin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(h)1-[[[2-(2,6-dimethylpiperidin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(i)1-[[[2-(4-hydroxy-4-phenyl-piperidin-1-yl)ethyl]amino]carbonyl]-α,.alpha.-diphenyl-4-piperidineacetamide.

(j)1-[[[2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethyl]amino]carbonyl]-.alpha.,α-diphenyl-4-piperidineacetamide,

(k)1-[[[2-(4-t-butoxycarbonyl-piperazin-1-yl)ethyl]amino]carbonyl]-α,.alpha.-diphenyl-4-piperidineacetamide,

(l)1-[[[2-(4-methyl-piperazin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(m)1-[[[2-(4-phenyl-piperazin-1-yl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide,

(n)1-[[[2-(4-phenylmethyl-piperazin-1-yl)ethyl]amino]carbonyl]-α,.alpha.-diphenyl-4-piperidineacetamide,and

(o)1-[[[2-(4-morpholinyl)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamide.

PHARMACOLOGY

The action of compounds of this invention in correcting cardiacarrhythmias or preventing cardiac arrhythmias is demonstrated by thefollowing procedures:

OUABAIN INDUCED ARRHYTHMIAS

Correcting of existing cardiac arrhythmias of ventricular origin iscarried out on (1) adult mongrel dogs which are under barbiturateanesthesia during the test. A Grass Model 7 Polygraph was used forrecording femoral arterial blood pressure (Statham P23AC Transducer) andthe electrocardiogram (Grass 7P4 Preamplifier). Ouabian was givenintravenously in an initial dose of 40 μg/kg and in a second dose of 20μg/kg 30 minutes after the first dose and in subsequent doses of 10μg/kg which are repeated at 15 min intervals as required for producingcardiac arrhythmias that persisted for at least 15 minutes. When thearrhythmias were established, the test compounds were administered byinfusion (Harvard Model 942 Infusion Pump) into a femoral vein at a rateof 1 mg/kg/min. Concentration of compound was adjusted according to theweight of the dog to allow a volume infusion of 1 ml/min. The compoundwas considered to be active as antiarrhythmic agent if reversion tosinus rhythm occurred which was maintained for at least 30 min.

CORONARY ARTERY LIGATION INDUCED ARRHYTHMIAS

Adult mongrel dogs which are in the conscious state were used for thetest and cardiac arrhythmias were induced by prior (22-24 hr) surgicalpreparation in which blood flow through a coronary artery was occludedby use of a constrictor device as reported by Smith et al, 1973. A GrassModel 79 Polygraph was used for recording the electrocardiogram (Grass7P4 Preamplifier).

The test compound was administered by infusion (Harvard Model 942Infusion Pump) into a saphenous vein to one group of dogs at a rate of0.5 mg/kg/min. Concentration of compound was adjusted according to theweight of the dog to allow a volume of infusion of 0.5 ml/min. The testcompound was administered orally by gavage to another group of dogs atdose levels of 10 through 40 mg/kg. The test compound was prepared indistilled water to give a total volume of 20 ml. Following theadministration of the test compound, the heart rate, number of ectopiccardiac beats per min, and the percent ectopic beats (ectopic beats/HRX100) were recorded at 15 min. intervals. The compound was consideredactive if it abolished the ectopic ventricular frequency and caused areturn to normal sinus rhythm within 2 hours of administration.

Data obtained demonstrating the antiarrhythmic activity of compounds ofFormula I are in Table.

                  TABLE 1                                                         ______________________________________                                        Effect of Compounds on Cardiac Arrhythmias in Dogs                                      Arrhythmia Model                                                                             Coronary Artery                                                  Ouabain Induced.sup.1                                                                      Ligation Induced.sup.2                               Compound    Correcting Dose,                                                                           Correcting Dose,                                     Example No. mg/kg, i.v.  mg/kg, i.v.                                          ______________________________________                                        1           --           17                                                   4           8-9          10-14                                                5           6.0          13                                                   ______________________________________                                         .sup.1 Cardiac arrhythmias produced by method of Lucchessi and Hardman,       1961, J. Pharmacol. Exp. Therap. 132, 372-381.                                .sup.2 Cardiac arrhythmias produced by modification of method of Harris,      1950, Circulation 1, 1318, as reported by Smith et al, 1973,                  Pharmacologist 15, 192.                                                       .sup.3 Calculated as free base.                                          

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

The invention further provides pharmaceutical compositions foradministration to a living animal body comprising, as activeingredients, at least one of the compounds according to the invention inassociation with a pharmaceutical carrier or excipient. The compoundsare thus presented in a therapeutic composition suitable for oral,rectal, parenteral or intracardial administration. Thus, for example,compositions for oral administration are preferably solids and can takethe form of capsules, tablets or coated tablets containing carriersconveniently used in the pharmaceutical art. Suitable tabletingexcipients include lactose, potato and maize starches, talc, gelatin andstearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient can be asterile, parenterally acceptable liquid; e.g., water, or a parenterallyacceptable oil; e.g., arachis oil contained in ampoules.

In compositions for rectal administration the carrier can comprise asuppository base; e.g., cocoa butter, or a glyceride.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage forms according to the invention. It isonly necessary that the active ingredient constitute an effectiveamount; i.e., such that a suitable effective dosage will be obtainedconsistent with the dosage form employed. The exact individual dosages,as well as daily dosages, will, of course, be determined according tostandard medical principles under the direction of a physician orveterinarian. Generally, the pharmacology on animals suggests the oraldosage effective to correct arrhythmias will be about 3 times that ofthe intravenous dosage. The animal data also suggest dosage requirementswill be about half that of quinidine for the more active compounds.

Based on the animal data, allowing for variation in species and severityof cardiac arrhythmias, unit dosages containing an amount of compoundequivalent to about 1 to about 100 mg/kg of body weight arecontemplated. Based on all of the above considerations, a choice in arange of unit oral dosages for humans of about 10 to about 1000 mg iscontemplated, preferably about 10 to 600 mg for a more active compoundsuch as Example 4. Daily dosages of about 30 to 2400 mg are contemplatedfor humans and obviously several unit dosage forms may be administeredat about the same time. However, the scope of the invention is not to belimited by these contemplations due to the uncertainty in transpositionsdiscussed above.

Examples of unit dosage compositions are as follows:

    ______________________________________                                        Capsules                                                                      Ingredients       Per Cap.                                                    ______________________________________                                        1. Active ingredient                                                                             10.0 mg.                                                   2. Lactose        146.0 mg.                                                   3. Magnesium Stearate                                                                            4.0 mg.                                                    ______________________________________                                    

Procedure

1. Blend 1, 2 and 3.

2. Mill this blend and blend again.

3. This milled blend is then filled into #1 hard gelatin capsules.

    ______________________________________                                        Tablets (10 mg)                                                               Ingredients       Mg./Tab.                                                    ______________________________________                                        1. Active ingredient                                                                            10.0 mg.                                                    2. Corn starch    20.0 mg.                                                    3. Kelacid        20.0 mg.                                                    4. Keltose        20.0 mg.                                                    5. Magnesium Stearate                                                                            1.3 mg.                                                    ______________________________________                                    

    ______________________________________                                        Tablets (50 mg)                                                               Ingredients      Mg/Tab.                                                      ______________________________________                                        1. Active Ingredient                                                                           50.0 mg.                                                     2. Milo starch   20.0 mg.                                                     3. Corn starch   38.0 mg.                                                     4. Lactose       90.0 mg.                                                     5. Calcium stearate                                                                             2.0 mg.                                                                      200.0 mg.                                                    ______________________________________                                    

Procedure

1. Blend 1, 2, 3 and 4.

2. Add sufficient water portionwise to the blend from step #1 withcareful stirring after each addition. Such additions of water andstirring continue until the mass is of a consistency to permit itsconversion to wet granules.

3. The wet mass is converted to granules by passing it through theoscillating granulator, using 8-mesh screen.

4. The wet granules are then dried in an oven at 140° F.

5. The dried granules are then passed through an oscillating granulator,using a 10-mesh screen.

6. Lubricate the dry granules with 0.5% magnesium stearate.

7. The lubricated granules are compressed on a suitable tablet press.

    ______________________________________                                        Intravenous Injection                                                         Ingredients       Per ml.                                                     ______________________________________                                        1. Active ingredient                                                                            1.0         mg.                                             2. pH 4.0 Buffer solution                                                                       q.s. to 1.0 ml.                                             ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step #1.

3. The sterile solution is now aseptically filled into sterile ampuls.

4. The ampuls are sealed under aseptic conditions.

    ______________________________________                                        Intramuscular Injection                                                       Ingredients         Per ml.                                                   ______________________________________                                        1. Active ingredients                                                                             5.0        mg.                                            2. Isotonic Buffer solution 4.0                                                                   q.s. to 1.0                                                                              ml.                                            ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step #1.

3. The sterile solution is now aseptically filled into sterile ampuls.

4. The ampuls are sealed under aseptic conditions.

    ______________________________________                                        Suppositories                                                                 Ingredients        Per Supp.                                                  ______________________________________                                        1. Active ingredient                                                                             10.0        mg.                                            2. Polyethylene Glycol 1000                                                                      1350.0      mg.                                            3. Polyethylene Glycol 4000                                                                      450.0       mg.                                            ______________________________________                                    

Procedure

1. Melt 2 and 3 together and stir until uniform.

2. Dissolve #1 in the molten mass from step 1 and stir until uniform.

3. Pour the molten mass from step 2 into suppository molds and chill.

4. Remove the suppositories from molds and wrap.

Therapeutic compositions having cardiac arrhythmia inhibiting activityin dosage unit form, comprising a pharmaceutical carrier and a cardiacarrhythmia inhibiting amount of a compound of Formula I or apharmaceutically acceptable acid addition salt thereof are therefore anembodiment of this invention.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, method, and compositions ofthe present invention without departing from the spirit or scopethereof, and it is therefore to be understood that the invention is tobe limited only by the scope of the appended claims.

What is claimed is:
 1. A compound selected from the group having theformula: ##STR17## wherein; n is selected from zero, one or two;X isselected from oxygen or sulfur; Z is selected from ##STR18## p isselected from 0 to 5 inclusive with the proviso that when Z is ##STR19##p is at least one; Y is selected from aminocarbonyl or cyano; Ar¹ andAr², which may be the same or different, are selected from the groupconsisting of phenyl or phenyl substituted by 1 to 3 radicals which maybe the same or different selected from loweralkyl, lower-alkoxy, halogenor trifluoromethyl; R is selected from hydrogen or loweralkyl; R¹, R²and R³ are selected from the group consisting of hydrogen, cycloalkyl,loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, orloweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted byhalogen, loweralkyl or loweralkoxy, and R¹, R² and R³ may be the same ordifferent; and when the side group ##STR20## is in the 3-position andAr¹ and Ar² are dissimilar, the diastereoisomers thereof; and thepharmaceutically acceptable acid addition salts thereof.
 2. The compoundof claim 1 which is1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 3. Thecompound of claim 1 which is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 4. Thecompound of claim 1 which is1-[[[(2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-piperidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 5. Thecompound of claim 1 which is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-αα-diphenyl-4-piperidineacetamide or a pharmaceutically acceptable acidaddition salt thereof.
 6. A compound selected from the group having theformula: ##STR21## wherein; n is selected from zero, one or two;X isselected from oxygen or sulfur; p is selected from 0 to 5 inclusive; Yis selected from aminocarbonyl or cyano; Ar¹ and Ar², which may be thesame or different, are selected from the group consisting of phenyl orphenyl substituted by 1 to 3 radicals which may be the same or differentselected from loweralkyl, loweralkoxy, halogen or trifluoromethyl; R isselected from hydrogen or loweralkyl; R¹, R² and R³ are selected fromthe group consisting of hydrogen, cycloalkyl, loweralkyl, phenyl, phenylsubstituted by halogen, loweralkyl, or loweralkoxy and phenyl-loweralkylwherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy,and R¹, R² and R³ may be the same or different; and when the side group##STR22## is in the 3-position and Ar¹ and Ar² are dissimilar, thediastereoisomers thereof; and the pharmaceutically acceptable acidaddition salts thereof.
 7. A compound selected from the group having theformula: ##STR23## wherein; n is selected from zero, one or two;X isselected from oxygen or sulfur; p is selected from 1 to 5 inclusive; Yis selected from aminocarbonyl or cyano; Ar¹ and Ar², which may be thesame or different, are selected from the group consisting of, phenyl orphenyl substituted by 1 to 3 radicals which may be the same or differentselected from loweralkyl, loweralkoxy, halogen or trifluoromethyl; R isselected from hydrogen or loweralkyl; R¹, R², and R³ are selected fromthe group consisting of hydrogen, cycloalkyl, loweralkyl, phenyl, phenylsubstituted by halogen, loweralkyl, or loweralkoxy and phenyl-loweralkylwherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy,and R¹, R² and R³ may be the same or different; and when the side group##STR24## is in the 3-position and Ar¹ and Ar² are dissimilar, thediastereoisomers thereof; and the pharmaceutically acceptable acidaddition salts thereof.
 8. A method of treating cardiac arrhythmias inan animal which comprises administering to said animal an effectiveamount of a compound having the formula: ##STR25## wherein; n isselected from zero, one or two;X is selected from oxygen or sulfur; Z isselected from ##STR26## p is selected from 0 to 5 inclusive with theproviso that when Z is ##STR27## p is at least one; Y is selected fromaminocarbonyl or cyano; Ar¹ and Ar², which may be the same or different,are selected from the group consisting of phenyl or phenyl substitutedby 1 to 3 radicals which may be the same or different selected fromloweralkyl, loweralkoxy, halogen or trifluoromethyl; R is selected fromhydrogen or loweralkyl; R¹, R² and R³ are selected from the groupconsisting of hydrogen, cycloalkyl, loweralkyl, phenyl, phenylsubstituted by halogen, loweralkyl, or loweralkoxy and phenyl-loweralkylwherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy,and R¹, R² and R³ may be the same or different; and when the side group##STR28## is in the 3-position and Ar¹ and Ar² are dissimilar, thediastereoisomers thereof; and the pharmaceutically acceptable acidaddition salts thereof.
 9. The method of claim 8 wherein the compound is1-[[(dimethylamino)methyl]-carbonyl]-α,α-diphenyl-3-pyrrolidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 10. Themethod of claim 8 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-αα-diphenyl-3-pyrrolidineacetamide or a pharmaceutically acceptable acidaddition salt thereof.
 11. The method of claim 8 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-piperidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 12. Themethod of claim 8 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 13. Amethod of treating cardiac arrhythmias in an animal which comprisesadministering to said animal an effective amount of a compound havingthe formula: ##STR29## wherein; n is selected from zero, one or two;X isselected from oxygen or sulfur; p is selected from 0 to 5 inclusive; Yis selected from aminocarbonyl or cyano; Ar¹ and Ar², which may be thesame or different, are selected from the group consisting phenyl orphenyl substituted by 1 to 3 radicals which may be the same or differentselected from loweralkyl, loweralkoxy, halogen or trifluoromethyl; R isselected from hydrogen or loweralkyl; R¹, R², and R³ are selected fromthe group consisting of hydrogen, cycloalkyl, loweralkyl, phenyl, phenylsubstituted by halogen, loweralkyl, or loweralkoxy and phenyl-loweralkylwherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy,and R¹, R² and R³ may be the same or different; and when the side group##STR30## is in the 3-position and Ar¹ and Ar² are dissimilar, thediastereoisomers thereof; and the pharmaceutically acceptable acidaddition salts thereof.
 14. A method of treating cardiac arrhythmias inan animal which comprises administering to said animal an effectiveamount of a compound having the formula: ##STR31## wherein; n isselected from zero, one or two;X is selected from oxygen or sulfur; p isselected from 1 to 5 inclusive; Y is selected from aminocarbonyl orcyano; Ar¹ and Ar², which may be the same or different, are selectedfrom the group consisting of phenyl or phenyl substituted by 1 to 3radicals which may be the same or different selected from loweralkyl,loweralkoxy, halogen or trifluoromethyl; R is selected from hydrogen orloweralkyl; R¹, R² and R³ are selected from the group consisting ofhydrogen, cycloalkyl, loweralkyl, phenyl, phenyl substituted by halogen,loweralkyl, or loweralkoxy and phenyl-loweralkyl wherein phenyl may besubstituted by halogen, loweralkyl or loweralkoxy, and R¹, R² and R³ maybe the same or different; and when the side group ##STR32## is in the3-position and Ar¹ and Ar² are dissimilar, the diastereoisomers thereof;and the pharmaceutically acceptable acid addition salts thereof.
 15. Atherapeutic composition for the treatment of cardiac arrhythmiascomprising (a) an effective amount of a compound selected from the grouphaving the formula: ##STR33## wherein; n is selected from zero, one ortwo;X is selected from oxygen or sulfur; Z is selected from ##STR34## or--CH₂ --; p is selected from 0 to 5 inclusive with the proviso that whenZ is ##STR35## p is at least one; Y is selected from aminocarbonyl orcyano; Ar¹ and Ar², which may be the same or different, are selectedfrom the group consisting of phenyl or phenyl substituted by 1 to 3radicals which may be the same or different selected from loweralkyl,loweralkoxy, halogen or trifluoromethyl; R is selected from hydrogen orloweralkyl; R¹, R² and R³ are selected from the group consisting ofhydrogen, cycloalkyl, loweralkyl, phenyl, phenyl substituted by halogen,loweralkyl, or loweralkoxy and phenyl-loweralkyl wherein phenyl may besubstituted by halogen, loweralkyl or loweralkoxy, and R¹, R² and R³ maybe the same or different; and when the side group ##STR36## is in the3-position and Ar¹ and Ar² are dissimilar, the diastereoisomers thereof;the pharmaceutically acceptable acid addition salts thereof; and (b) apharmaceutically acceptable carrier therefor.
 16. The therapeuticcomposition of claim 15 wherein the compound is1-[[(dimethylamino)methyl]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 17. Thetherapeutic composition of claim 15 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-pyrrolidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 18. Thetherapeutic composition of claim 15 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-3-piperidinoacetamideor a pharmaceutically acceptable acid addition salt thereof.
 19. Thetherapeutic composition of claim 15 wherein the compound is1-[[[2-(dimethylamino)ethyl]amino]carbonyl]-α,α-diphenyl-4-piperidineacetamideor a pharmaceutically acceptable acid addition salt thereof.
 20. Atherapeutic composition for the treatment of cardiac arrhythmiascomprising (a) an effective amount of a compound selected from the grouphaving the formula: ##STR37## wherein; n is selected from zero, one ortwo;X is selected from oxygen or sulfur; p is selected from 0 to 5inclusive; Y is selected from aminocarbonyl or cyano; Ar¹ and Ar², whichmay be the same or different, are selected from the group consisting ofphenyl or phenyl substituted by 1 to 3 radicals which may be the same ordifferent selected from loweralkyl, loweralkoxy, halogen ortrifluoromethyl; R is selected from hydrogen or loweralkyl; R¹, R² andR³ are selected from the group consisting of hydrogen, cycloalkyl,loweralkyl, phenyl, phenyl substituted by halogen, loweralkyl, orloweralkoxy and phenyl-loweralkyl wherein phenyl may be substituted byhalogen, loweralkyl or loweralkoxy, and R¹, R² and R³ may be the same ordifferent; and when the side group ##STR38## is in the 3-position andAr¹ and Ar² are dissimilar, the diastereoisomers thereof; thepharmaceutically acceptable acid addition salts thereof; and (b) apharmaceutically acceptable carrier therefor.
 21. A therapeuticcomposition for the treatment of cardiac arrhythmias comprising (a) aneffective amount of a compound selected from the group having theformula: ##STR39## wherein; n is selected from zero, one or two;X isselected from oxygen or sulfur; p is selected from 1 to 5 inclusive; Yis selected from aminocarbonyl or cyano; Ar¹ and Ar², which may be thesame or different, are selected from the group consisting of phenyl orphenyl substituted by 1 to 3 radicals which may be the same or differentselected from loweralkyl, loweralkoxy, halogen or trifluoromethyl; R isselected from hydrogen or loweralkyl; R¹, R² and R³ are selected fromthe group consisting of hydrogen, cycloalkyl, loweralkyl, phenyl, phenylsubstituted by halogen, loweralkyl, or loweralkoxy and phenyl-loweralkylwherein phenyl may be substituted by halogen, loweralkyl or loweralkoxy,and R¹, R² and R³ may be the same or different; and when the side group##STR40## is in the 3-position and Ar¹ and Ar² are dissimilar; thediastereoisomers thereof; the pharmaceutically acceptable acid additionsalts thereof; and (b) a pharmaceutically acceptable carrier therefor.